INTERACTOMICS RAM SAMUDRALA ASSOCIATE PROFESSOR UNIVERSITY OF WASHINGTON NIH DIRECTOR’S PIONEER...
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Transcript of INTERACTOMICS RAM SAMUDRALA ASSOCIATE PROFESSOR UNIVERSITY OF WASHINGTON NIH DIRECTOR’S PIONEER...
INTERACTOMICS
RAM SAMUDRALAASSOCIATE PROFESSOR
UNIVERSITY OF WASHINGTON
NIH DIRECTOR’S PIONEER AWARD 2010
How does the genome of an organism specifyits behaviour and characteristics?
How can we use this information to improvehuman health and quality of life?
COMPUTATIONAL ANALYSIS OF NOVEL DRUG OPPORTUNITIESTHE CANDO TEAM
cando.compbio.washington.edu
GENOME SEQUENCE TO PROTEIN AND PROTEOME…STRUCTURE FUNCTION
SYSTEMS
INFRASTRUCTURE APPLICATIONS
EVOLUTION
THERAPEUTICS
NANOTECHNOLOGY
RICE
DESIGN
INTERACTION
COMPOUND
DNA/RNAPROTEIN
SHOTGUN DRUG REPURPOSINGALL KNOWN DRUGS (~5,000 FROM FDA)
ALL TARGETS WITH KNOWN STRUCTURE (~80,000+)
+
FRAGMENT BASEDDOCKING WITH DYNAMICS
(~120,000,000)
PRIORITISEDHITS
MACHINE LEARNING
M Lagunoff (UW), W Van Voorhis (UW),S Michael (FCGU), J Mullins (UW), G Wong/A Mason/L Tyrell (U Alberta), W Chantratita/P Palittapongarnpim (Thailand)Many more at cando.compbio.washington.edu
herpes, malaria, dengue hepatitis C, dental cariesHIV, HBRV, XMRV, rabies,encephalitis, cholera, tuberculosis, various cancers,and many more: cando.compbio.washington.edu
CLINICAL STUDIES/APPLICATION
INITIAL CLINICAL TRIALS
IN VITROSTUDIES
IN VIVO STUDIES
DISSOCIATION CONSTANTS (KD)(~300-500 + collaborations)
Multitarget protocol: 2,344 → 16 → 6 ≤ 1 µM ED50HTS protocol: 2,687 → 19 ≤ 1 µM ED50HTS protocol: 2,160 → 36 ≤ 1 µM ED50Docking protocol: 355,000 → 100 → 1 ≤ 10 µM ED50Docking protocol: 241,000 → 84 → 4 ≤ 10 µM ED50
14 targets MALARIA
Trends in Pharmacological Sciences, 2010.
DENGUE
PLoS Neglected Tropical Diseases, 2010.
2/4 ≤ µM ED50against dengue virus
Prediction #1Prediction #2
Viral E protein
PROSPECTIVE PRELIMINARY VERIFICATION
Observed:Function is inactivated.
KD protease ligand ≤ μMKD protease dimer ≤ μM
Experiment 1Experiment 2
HERPES(HSV, CMV, KSHV)
Predicted protease (dimer) + inhibitor:
He
rpe
s v
ira
l lo
ad
Lagunoff/ Van Voorhis/ Michael
NEISSERIA MENINGITIDISfactor H binding protein from Neisseria meningitidis mimics host carbohydrates and recruits host factor H to protect against the complement immune response
Neisseria meningitidis factor H binding protein
Homo sapiens factor H
Schneider et al. Nature, 2009.
Topamax
Treatement of epilepsy
Voacamine
Anti malarial agent
Loop movement breaks the interface Chopra/White
ACKNOWLEDGEMENTS
•Adrian Laurenzi•Brian Buttrick•Emilia Gan•Ersin Emre Oren•Gaurav Chopra•George White•Haychoi Taing•Helen Yu•Hernan Zamalloa•Jason North•Jeremy Horst•Ling-Hong Hung•Matthew Clark•Manish Manish•Michael Zhou •Nalini Schaduangat•Omid Zarei•Raymond Zhang•Sai Paul•Sergey Ovchinnikov•Thomas Wood
Current group members:•Aaron Chang•Aaron Goldman•Brady Bernard•Chuck Mader•Cyrus Hui•David Nickle•Duangdao Wichadukul•Duncan Milburn •Ekachai Jenwitheesuk•Gong Cheng •Imran Rashid•Jason McDermott•Juni Lee•Kai Wang•Marissa LaMadrid•Michael Inouye•Michael Shannon•Michal Guerquin•Nipa Jongkon
Past group members:•Rob Braiser•Renee Ireton•Shu Feng•Sarunya Suebtragoon•Shing-Chung Ngan•Shyamala Iyer•Siriphan Manocheewa•Somsak Phattarasukol•Stewart Moughon•Tianyun Liu•Vanessa Steinhilb•Vania Wang•Weerayuth Kittichotirat•Yi-Ling Cheng•Zach Frazier
CANDO TEAM MEMBERS IN BLUE:CURE OR TREAT DISEASES CURRENTLY UNTREATED
ACKNOWLEDGEMENTS
Funding agencies:•National Institutes of Health•National Science Foundation
-DBI-IIS
•Searle Scholars Program•Puget Sound Partners in Global Health•Washington Research Foundation•UW
-Advanced Technology Initiative-TGIF
•BGI/U Alberta-Gane Wong-Jun Yu-Jun Wang-Andrew Mason-Lorne Tyrell
•BIOTEC/KMUTT•Mahidol University
- Prasit Palittapongarrnpim- Wasun Chantratita
•MSE-Mehmet Sarikaya-Candan Tamerler -et al.
•UW Microbiology-James Staley-John Mittler-Michael Lagunoff-Roger Bumgarner-Wesley Van Voorhis-et al.
Collaborators:
Budget:• ~US$1 million/year total costs